Gammaherpesviruses, such as Epstein Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus are important human pathogens, associated with lymphoproliferative disorders and various maligancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and Kaposi's sarcoma. The initial lytic infection is efficiently cleared, but the virus establishes life-long latency, effectively hiding from the immune system. Periodic viral reactivation occurs sporadically, but is kept in check by host mechanisms of immune control. CD8+ T cells have been shown to be important for control of EBV, but the mechanisms are poorly understood. In the current proposal, we will exploit a new mouse model, murine gammaherpesvirus-68, MHV-68, to study basic mechanisms of immune control of this important class of viruses. Accumulating data from our laboratory and others show that MHV-68 latency is harbored in multiple cell types and anatomical sites. Therefore, an essential first step in characterizing immune control is to characterize reservoirs of latency, and determine mechanisms for maintaining the latent load, which will be addressed in Aims 1 and 2 of the current proposal. Taking this information into account, we will then examine immune mechanisms for controlling latency and preventing viral recrudescence in Aim 3. This is important for human health, as loss of immune control as a consequence of AIDS or post-transplant immunosuppression is associated with increased latent load and the onset of disease. The availability of an easily manipulated experimental mouse model is a major advance in the field, and allows fundamental mechanisms to be addressed. It is anticipated that the basic information gathered in this proposal will provide insight into the mechanisms of immune control of the clinically-relevant human gammaherpesviruses.